1. FIELD OF THE INVENTION
This invention relates to superoxide dismutase derivatives, a method of producing the same and medicinal use of the same.
2. DESCRIPTION OF THE PRIOR ARTS
Superoxide dismutase (hereinafter abbreviated as SOD) has been known so far as an enzyme occurring widely in living organisms, such as animals, plants and microbes, and decomposing superoxide which is harmful to living organisms. Recently, attempts have been made to use isolated SOD as an anti-inflammatory agent [Farumashia, 17, 411 (1981); Current Therapeutic Research, 16, 706 (1974)]. The use of SOD in the treatment of intractable radiation-induced colitis or in the prevention and treatment of gastric ulcer has also been studied [Jikken Igaku (Experimental Medicine), 4 (12), 39 (1986)].
As is clear from the results of a test example to be described later herein, human-type SOD is substantially lacking in anti-inflammatory activity and has very weak anti-ulcer activity.
It is said that the plasma half-life of intravenously administered SOD is only about 4 to 6 minutes; SOD is rapidly metabolized and excreted into urine. For prolonging the plasma half-life of SOD, attempts have been made to convert SOD to a giant molecule by modifying with Ficoll, polyethylene glycol or rat albumin. However, in the Ficoll- or polyethylene glycol-modified SOD, the enzymatic activity of SOD is markedly decreased, and the rat albumin-modified SOD has antigenicity. It has been reported that inulinmodified SOD has a reduced SOD activity as compared with unmodified SOD but has a much prolonged half-life in plasma [Japanese Kokai Tokkyo Koho No. 58-32826]. However, these modified SOD species have problems in their practical use for the above reasons or with respect to the decrease in tissue permeability due to the increase in molecular size.
It is an object of the invention to provide novel superoxide dismutase derivatives in which the enzymatic activity of SOD is substantially maintained with the plasma half-life being significantly prolonged as compared with SOD, without increasing the molecular size of SOD.
Another object of the invention is to provide novel and safe superoxide dismutase derivatives which have pharmacological activities such as anti-inflammatory, ischemic damage-preventing and cerebral edema-preventing activities.
A further object of the invention is to provide a method of producing the above-mentioned superoxide dismutase derivatives.
A still further object of the invention is to provide medicinal uses of said superoxide dismutase derivatives, for example as anti-inflammatory agents, protective agents against ischemic damages and agents for treating cerebral edema.
These objects as well as other objects and advantages of the present invention will become apparent to those skilled in the art from the following detailed description.